Studies of vaccinated mice and humans who are putatively resistant to reinfection with Schistosoma mansoni indicate that protection is dependent on induction of Th1 cells or IgE antibodies (Ab) regulated by Th2-type cytokines such as IL-4. Recent work indicates that CD28/CTLA-4 molecules on T cells and B7 on APC are critical in induction and expansion of Th cells and avoidance of Ag-specific unresponsiveness. Our preliminary studies of CD4+ cells demonstrate that repeated engagement of CD28 biases towards recall of Th2 responses and that S. mansoni-infected or egg- inoculated CD28 knockout mice and CTLA-4 Ig treated normal mice have significantly reduced Ag-specific Th2 but not Th1 cytokine production. To investigate how the CD28/CTLA-4 costimulatory pathway and relevant cytokines can be modified to enhance the efficacy of a vaccine against schistosomiasis, the following specific aims are proposed. SPECIFIC AIM 1. To determine the role of B7:CD28/CTLA-4 interactions in protection induced by irradiated cercariae. This objective examines whether CTLA-4 Ig, which interferes with B7:CD28/CTLA-4 interaction, can modify S. mansoni-specific Th responses and worm loads in mice vaccinated 1 or 2 times with radiation-attenuated cercariae. Analogous studies will be performed in IL-4 and CD28 knockout mice. SPECIFIC AIM 2. To examine whether modification of B7:CD28/CTLA-4 interaction in vivo alters protective immunity induced by the vaccine candidate molecule IrV-5. This aim will test the hypothesis that selective induction of Th2 subset responses to recombinant IrV-5 by alteration of the APC-T cell costimulatory pathway enhances its protective efficacy. SPECIFIC AIM 3. To establish whether vaccination with DNA plasmids encoding IrV-5 with or without B-7 or IL-4 induce resistance to infection. DNA plasmids encoding the Ag IrV-5 with and without constructs that encode B7 or IL-4 will be used to vaccinate mice by the intramuscular or intradermal route. Resistance to infection, Ag-specific T cell and Ab isotype responses will be evaluated and compared with controls given plasmids not encoding IrV-5. These studies will advance our understanding of how manipulation of APC-T cell costimulatory pathways can be used to facilitate development of a vaccine against schistosomiasis and other parasitic infections.